title: Caspase signalling controls microglia activation and neurotoxicity.
abstract: Activation of microglia and inflammation-mediated neurotoxicity are suggested to play a decisive role in the pathogenesis of several neurodegenerative disorders. Activated microglia release pro-inflammatory factors that may be neurotoxic. Here we show that the orderly activation of caspase-8 and caspase-3/7, known executioners of apoptotic cell death, regulate microglia activation through a protein kinase C (PKC)-δ-dependent pathway. We find that stimulation of microglia with various inflammogens activates caspase-8 and caspase-3/7 in microglia without triggering cell death in vitro and in vivo. Knockdown or chemical inhibition of each of these caspases hindered microglia activation and consequently reduced neurotoxicity. We observe that these caspases are activated in microglia in the ventral mesencephalon of Parkinson's disease (PD) and the frontal cortex of individuals with Alzheimer's disease (AD). Taken together, we show that caspase-8 and caspase-3/7 are involved in regulating microglia activation. We conclude that inhibition of these caspases could be neuroprotective by targeting the microglia rather than the neurons themselves.
authors.affiliation: Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet, 171 76, Stockholm, Sweden.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Burguillos
authors.forename: Tomas
authors.initials: T
authors.lastname: Deierborg
authors.forename: Edel
authors.initials: E
authors.lastname: Kavanagh
authors.forename: Annette
authors.initials: A
authors.lastname: Persson
authors.forename: Nabil
authors.initials: N
authors.lastname: Hajji
authors.forename: Albert
authors.initials: A
authors.lastname: Garcia-Quintanilla
authors.forename: Josefina
authors.initials: J
authors.lastname: Cano
authors.forename: Patrik
authors.initials: P
authors.lastname: Brundin
authors.forename: Elisabet
authors.initials: E
authors.lastname: Englund
authors.forename: Jose L
authors.initials: JL
authors.lastname: Venero
authors.forename: Bertrand
authors.initials: B
authors.lastname: Joseph
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology / Q000473:pathology; D000818:Animals; D053148:Caspase 3 / Q000172:deficiency / Q000378:metabolism; D053179:Caspase 7 / Q000172:deficiency / Q000378:metabolism; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D061945:Caspase Inhibitors; D020169:Caspases / Q000172:deficiency / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism; D004789:Enzyme Activation; D005625:Frontal Lobe / Q000201:enzymology / Q000473:pathology; D055785:Gene Knockdown Techniques; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D017072:Neostriatum / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D010300:Parkinson Disease / Q000201:enzymology / Q000473:pathology; D051745:Protein Kinase C-delta / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D013378:Substantia Nigra / Q000201:enzymology / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D061945:Caspase Inhibitors; D008070:Lipopolysaccharides; D051197:Toll-Like Receptor 4; D051745:Protein Kinase C-delta; D053148:Caspase 3; D053179:Caspase 7; D053181:Caspase 8; D020169:Caspases; D004298:Dopamine